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S1501 Carvedilol in Preventing Cardiac Toxicity in Patients With Metastatic HER-2-Positive Breast Cancer

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ClinicalTrials.gov Identifier: NCT03418961
Recruitment Status : Recruiting
First Posted : February 1, 2018
Last Update Posted : August 31, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group

Brief Summary:
This phase III trial studies how well carvedilol works in preventing cardiac toxicity in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer that has spread to other places in the body. A beta-blocker, such as carvedilol, is used to treat heart failure and high blood pressure, and it may prevent the heart from side effects of chemotherapy.

Condition or disease Intervention/treatment Phase
Cardiotoxicity HER2/Neu Positive Metastatic Malignant Neoplasm in the Brain Recurrent Breast Carcinoma Stage IV Breast Cancer AJCC v6 and v7 Drug: Carvedilol Other: Laboratory Biomarker Analysis Other: Patient Observation Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 817 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: Prospective Evaluation of Carvedilol in Prevention of Cardiac Toxicity in Patients With Metastatic HER-2+ Breast Cancer, Phase III
Actual Study Start Date : September 15, 2017
Estimated Primary Completion Date : February 1, 2023
Estimated Study Completion Date : February 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (carvedilol)
Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive carvedilol PO BID. Courses repeat every 12 weeks for 108 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Carvedilol
Given PO
Other Name: Coreg

Other: Laboratory Biomarker Analysis
Correlative studies

Active Comparator: Arm II (no intervention)
Patients not taking beta blocker, ARB, or ACE inhibitor at registration receive no study intervention for up to 108 weeks.
Other: Laboratory Biomarker Analysis
Correlative studies

Active Comparator: Arm III (observation)
Patients undergo observation for up to 108 weeks.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Patient Observation
Undergo observation
Other Names:
  • Active Surveillance
  • deferred therapy
  • expectant management
  • observation
  • Watchful Waiting




Primary Outcome Measures :
  1. Time to the first identification of cardiac dysfunction [ Time Frame: Up to 108 weeks ]
    Real-time, blinded, central echocardiography (ECHO) read as a decrease in the left ventricular ejection fraction (LVEF) of >= 10 percentage points from baseline to a value of < 50% OR decrease of LVEF by >= 5 percentage points from baseline to LVEF < 50% in those baselines having a baseline LVEF of 50-54%. The distributions of time to cardiac dysfunction will be described using cumulative incidence estimates, with the statistical significance of treatment arm differences assessed by Cox and Fine-Gray regression models with adjustment for stratification factors. Gray's test will also be applied


Secondary Outcome Measures :
  1. Incidence of adverse events associated with beta blocker treatment [ Time Frame: Up to 108 weeks ]
    Adverse events associated with beta blocker treatment will be assessed.

  2. Rate of first interruption of trastuzumab [ Time Frame: Up to 108 weeks ]
    The distributions of time to interruption of trastuzumab-based therapy will be described using cumulative incidence estimates, with the statistical significance of treatment arm differences assessed by Cox and Fine-Gray regression models with adjustment for stratification factors. Gray?s test will also be applied to the primary endpoint to assess whether the results are sensitive to different model assumptions.

  3. Rate of death [ Time Frame: Up to 108 weeks ]
    Will compare rate of death from competing causes between treatment arms via Cox regression to evaluate whether those rates impact the primary analysis comparison.

  4. Time to first occurrence of cardiac event [ Time Frame: Up to 108 weeks ]
    any of the following treating physician documented events requiring hospitalization or medical treatment, and subsequent temporary or permanent discontinuation of trastuzumab- based HER-2 targeted therapy: arrhythmia, unstable angina, non-ST segment elevated myocardial infarction, myocardial infarction, or congestive heart failure.

  5. Drug adherence [ Time Frame: Up to 108 weeks ]
    Patients on the active arm will be asked to record study drug consumption on a monthly intake calendar. Amount of study drug taken among patients randomized to the active arm and study drug adoption among patients randomized to the no intervention arm (i.e., contamination) will be recorded by study site staff on a case report form at each follow-up visit to assess the sensitivity of the primary treatment effect to observed conditions.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • STEP 1 REGISTRATION
  • Patients must have metastatic breast cancer and be initiating within 7 days of step 1 registration or continuing trastuzumab?based HER-2 targeted therapy without concurrent anthracyclines in first or second line setting; patients may have brain metastasis; there is no limit for number of doses of HER-2 targeted therapy prior to registration; examples of eligible HER-2 targeted therapy:

    • Trastuzumab
    • Trastuzumab + chemotherapy or hormonal therapy
    • Trastuzumab + other HER-2 targeted agent with or without chemotherapy (such as pertuzumab)
    • Ado-trastuzumab (Kadcyla)
    • NOTE: Patients on lapatinib without trastuzumab are not eligible; planned treatment with concurrent HER-2 targeted therapy and anthracyclines is not permitted
  • Patients must be at increased risk for cardiotoxicity defined by at least one of the following:

    • Previous anthracycline exposure, OR
    • 1 or more of the following risk factors for heart disease:

      • Left ventricular ejection fraction (LVEF) 50-54% by local echocardiography (ECHO) read
      • Age >= 65
      • Body mass index (BMI) >= 30 kg/m^2
      • Current or prior anti-hypertensive therapy
      • Diagnosis of coronary artery disease (CAD)
      • Diabetes mellitus
      • Atrial fibrillation/flutter
  • Patients must not have taken within 21 days prior to step 1 registration, be currently taking at the time of step 1 registration, or planning to take once registered to step 1 a beta blocker, ARB, or ACE inhibitor in order to be randomized (Arms 1 and 2)

    • Patients currently taking a beta blocker, ARB, or ACE inhibitor at the time of step 1 registration are eligible to register for the non-randomized observational cohort (Arm 3)
  • Patients must not be currently taking or planning to take during study treatment the following medications:

    • B2 agonists
    • Bosutinib
    • Ceritinib
    • Floctafenine
    • Methacholine
    • Pazopanib
    • Rivastigmine
    • Vincristine
    • Silodosin
  • Patients must have a Zubrod Performance status of 0-2
  • Patients must have a complete physical examination and medical history within 28 days prior to registration
  • Patients must have LVEF >= 50% by 2-dimensional (D) echocardiogram within 28 days prior to registration; the echocardiogram must be obtained from a S1501 validated ECHO laboratory (lab) and submitted for central review by the S1501 ECHO core lab; ECHO should not be submitted for central read until patient has been otherwise deemed eligible
  • Serum bilirubin < 3.0 x institutional upper limit of normal (IULN)
  • Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) < 5.0 x IULN
  • Patients must have electrocardiogram with corrected QT (QTc) with correction within 28 days prior to registration
  • Patients must have a systolic blood pressure >= 80 mm Hg within 14 days prior to registration
  • Patients must not be dialysis dependent
  • Patients must be able to swallow tablets
  • Patients must not have uncontrolled asthma
  • Patients must not co-enroll on other treatment trials
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer on active surveillance, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  • Patients must not be pregnant or nursing due to potential fetal or nursing infant harm; women/men of reproductive potential must have agreed to use an effective contraceptive method, a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • Patients must be willing to submit blood specimens
  • Sites must seek additional patient consent for the future use of specimens
  • Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • STEP 2 REGISTRATION (Randomization)
  • Patients must not be registered to step 2 until receiving confirmation from the ECHO Core Lab that the patient?s LVEF by echocardiogram was >= 50% by central review; patients must be registered within 5 calendar days of receiving the e-mail notification
  • Site must verify that there is no known change in the step 1 eligibility since initial registration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03418961


  Show 523 Study Locations
Sponsors and Collaborators
Southwest Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Justin Floyd Southwest Oncology Group

Responsible Party: Southwest Oncology Group
ClinicalTrials.gov Identifier: NCT03418961     History of Changes
Other Study ID Numbers: S1501
NCI-2016-01047 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1501 ( Other Identifier: SWOG )
SWOG-S1501 ( Other Identifier: DCP )
UG1CA189974 ( U.S. NIH Grant/Contract )
First Posted: February 1, 2018    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Cardiotoxicity
Neoplasms, Second Primary
Brain Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Carvedilol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists